Playing 24 games (13 started) in 2001, Arroyo complied with a 5-7 record and a 5.09 ERA. Limited in playing time due to injuries and time in the minors, Arroyo played nine games (four started) in 2002 going 2-1 with a 4.00 ERA.

Before the 2003 season, the Boston Red Sox claimed Arroyo from the Pirates off of waivers.[6] Pitching for the Pawtucket Red Sox of the Class AAAInternational League, Arroyo pitched the fourth nine-inning perfect game in the 121-year history of the International League on August 10, 2003. He struck out nine, and went to a three-ball count to just three hitters all game long. He made 6 appearances in the majors with his first career save and a 2.08 ERA.

Arroyo improved in 2004, jumping from middle relief to be the Red Sox No. 5 starter. On July 24, 2004, Arroyo hit Alex Rodriguez with a pitch, which led to a bench-clearing brawl. He compiled a 10–9 mark with a 4.03 ERA in ​1782⁄3 innings, while posting a respectable 3.02 strikeout-to-walk ratio (142-to-47). He led the majors with hitting batsmen with pitches, totaling 20 hit by pitches.

Arroyo also got his first & only championship title when the Red Sox won the World Series against the St. Louis Cardinals. Arroyo made two starts and four relief appearances in the postseason, compiling a 0–0 record with two holds and a 7.82 ERA for the 2004 World Series champion Red Sox. During Game 6 of the 2004 American League Championship Series, Alex Rodriguez knocked away the ball from Arroyo's glove while attempting to apply a tag. The umpires reversed the ruling that Rodriguez was safe, forcing Derek Jeter to return to first base and calling Rodriguez out on the play for runner interference.

Arroyo's most productive season so far came in 2005, when he posted career highs up to that time in wins (14), starts (32), innings (205.1) and pitching appearances (35). He also excelled at holding runners, as he only gave up five stolen bases. Before the 2006 season, Arroyo signed a three-year, $11.25 million contract with the Red Sox.[7] Arroyo said the deal was a "hometown discount" and agreed to the terms against the advice of his agent.[8][9]

During spring training before the 2006 season, the Red Sox traded Arroyo to the Cincinnati Reds for outfielderWily Mo Peña.[10] 2006 was a high point in Arroyo's career. Highlights of the season included a league-leading ​2402⁄3 innings pitched, his first selection to an All-Star game, as well as his first career shutout in the major leagues. He finished the 2006 year going 14-11 with an ERA of 3.29.

In February 2007, Arroyo signed a contract extension with the Cincinnati Reds which kept him with the organization through the 2010 season, with an option for the year 2011.[7] He finished the 2007 season 9-15 and a 4.23 ERA.

Arroyo pitched exactly 200 innings in 2008 by going 15-11 with a 4.77 ERA. During the season, Arroyo gave up 6 or more runs in a game 7 times in 34 starts including a game on 6/24 against the Toronto Blue Jays where he gave up 11 earned runs in 1 inning of work (he pitched into the second inning without recording an out).

Arroyo was diagnosed with carpal tunnel syndrome in his pitching hand during the 2008–09 offseason. As a result, he missed games during the 2009 spring training, as well as being advised to stop playing guitar until the symptoms disappeared. After a sub-par first half of the 2009 season, Arroyo turned in an excellent second half, lowering his ERA from the 5's to the 3's, throwing multiple shutouts and complete games, and putting himself in position to be the Reds top starter in 2010 since Edinson Vólquez, the #1 starter in 2009, was out for the start of the season following Tommy John surgery. Arroyo finished the 2009 year with 2 shutouts, a 15-13 record, and a 3.84 ERA.

In 2010, Arroyo was chosen as the #2 starter in the Reds' first playoff series in 15 years. He pitched ​51⁄3 innings against the Philadelphia Phillies, allowing one earned run and leaving with the lead. However, he would earn a no-decision as the Reds went on to lose the game. Arroyo won his first Gold Glove on November 10, 2010, the first by a Reds pitcher since Harvey Haddix in 1958. He finished the 2010 year 17-10 and a 3.88 ERA.

The Reds exercised the 2011 option on Arroyo's contract on November 3, 2010.[11] After exercising his option, the Reds and Arroyo agreed on a three-year, $35 million contract extension, keeping him with the team through 2013.

On March 26, 2011 Arroyo was diagnosed with mononucleosis, a condition where there is a high lymphocytes count in the blood from an Epstein-Barr virus (EBV) infection.

Arroyo finished the 2011 season 9-12 and a 5.07 ERA. He led the Majors with home runs allowed as he surrendered a total of 46 home runs.

Arroyo finished the 2012 season by going 12-10 with a 3.74 ERA. Arroyo was chosen by Reds' manager Dusty Baker to start Game 2 of the 2012 National League Division Series versus the San Francisco Giants. He took a perfect game into the fifth inning, and allowed only two base-runners (a base hit with two outs in the fifth, and a walk in the seventh) in seven scoreless innings. The Reds won the game 9-0 to take a 2-0 series lead. The win was Arroyo's first in thirteen postseason appearances, including five starts.

Arroyo finished the 2013 season with an ERA of 3.79 and a win-loss record of 14-12. He also was the league leader in home runs allowed, giving up 32 long balls. Although the numbers paint a picture of a subpar pitching year, Arroyo managed to throw one shutout and two complete games in his age 36 season. In the offseason Bronson Arroyo elected to test free agency.

On February 7, 2014, the Diamondbacks agreed to terms with Arroyo on a 2-year contract with $23.5 million guaranteed.[12][13]

On June 16, Arroyo was placed on the disabled list for the first time in his career, after leaving a start early against the Dodgers with an elbow injury.[14] It was announced on July 7 that Arroyo would be undergoing Tommy John surgery to repair a torn UCL, forcing him out for the remainder of the 2014 season. In 14 starts of the 2014 year, he went 7-4 with a 4.08 ERA.

On January 26, 2016, Arroyo signed a minor league contract with the Washington Nationals that included an invitation to major league spring training.[18][19] He pitched only 9 innings in the organization, in the Gulf Coast League, and was shut down due to elbow soreness.
On October 11, 2016, Arroyo was released.

Arroyo revealed that his previous elbow problems have been relieved by stem-cell injections he received in August.[20] On February 2, 2017, Arroyo signed a minor league contract with the Cincinnati Reds that included an invitation to spring training.[20][21] On June 19, Arroyo was placed on the 10-day disabled list with a right shoulder injury, and he admitted that he was contemplating retirement, stating "I don't see myself ponying it up next year."[22][23] Arroyo declined the opportunity to pitch one inning in September to close out his career, as he wanted to give a chance to a younger pitcher. On September 23, the Reds honored Arroyo with "Kickin' it With Bronson" night. Prior to the game, a ceremony was held with video tributes from manager Bryan Price and singer Eddie Vedder.[24] After the game, Arroyo held a concert on the field, performing Pearl Jam covers with his band. Arroyo ended the season with a 3–6 record and 7.35 ERA in 14 starts.[25] On September 24, he officially announced his retirement.[26]

A day after reports claimed former Red Sox teammate David Ortiz was among 104 Major League players to have failed drug tests in 2003, Arroyo revealed he had used androstenedione and amphetamines in his career. Bronson Arroyo remarked that he would not be surprised if he was among the 104 players that failed tests, as he suspected the androstenedione he was taking may have been tainted with steroids.[27]

Arroyo's fastball is in the 85–89 miles per hour range. While it is considered average among major league pitchers, his fastball has excellent movement and Arroyo is adept at "spotting" it. He also throws a hard slider that moves away from right-handed batters, and a straight changeup as well. Arroyo's best pitch is his curveball. He throws the pitch from multiple arm angles and is known to throw it in any count. The angle of the curveball itself can vary from a straight 12–6 to a sweeping 1–7. Arroyo's delivery is somewhat unusual; he incorporates a large leg kick in his pitching motion, extending his front leg completely straight and lifting it up to a level above his waist before delivering the ball. His kick often appears to reach head level and deceives hitters with its exaggerated motion. From the stretch position with runners on base, his leg-kick is much less pronounced and his delivery to home plate is very quick by major league standards. As a result, Arroyo is one of the better pitchers at holding runners on base.

Arroyo appears as a vocalist on the song "Since You" on Chad Perrone's album, Wake.[28]

Bronson made his public debut on stage in January 2004 at the Hot Stove Cool Music fundraiser at the Paradise Rock Club in Boston. He performed a cover of Pearl Jam's "Black" with teammate Kevin Millar. He later performed full sets at four other Hot Stove Cool Music events with a full band that featured saxophonist Elan Trotman and two members of Gnarls Barkley (drummer Eric Gardner and guitarist Clint Walsh).